Pharmacological chaperone treatment with Cystadane for aspartylglucosaminuria: an open-label, phase 1b/2, clinical trial

Abstract Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by a deficiency of the enzyme aspartylglucosaminidase (AGA) that is involved in glycoprotein breakdown. In the absence of this enzyme, glycoasparagines accumulate in the tissues and body fluids of the patients. No treatments targeting the disease cause are currently available. Our earlier findings show that betaine (tri-methyl glycine) functions as a pharmacological chaperone for the mutated AGA enzyme, resulting in an increased AGA activity in patient cells with pathogenic AGA missense variants. Here, we have carried out a phase 1b/2, open label clinical study (EudraCT number 2017-000645-48) with a clinically approved betaine product, Cystadane, in 21 Finnish AGU patients aged between 7.5 and 15 years at study begin, and homozygous for a specific missense variant. Cystadane was orally administrated for 48 months using a dose escalation strategy with a 3-month treatment break after the first year. The results of our study show that betaine is safe and well tolerated in AGU, and use of betaine results in a significant reduction of glycoasparagines in the urine, the primary endpoint of the study, as well as in a concomitant increase in serum AGA activity (a secondary endpoint). Exploratory neuropsychological findings showed significant improvements in some domains of the Wechsler’s Intelligence Scale for Children IV. Magnetic resonance imaging demonstrated that iron accumulation in specific thalamic regions of the patients is reduced due to betaine treatment. Our positive results encourage larger clinical trials with betaine in AGU.